D-Cycloserine (“DCS”) has long been clinically approved and used as an antibiotic to treat tuberculosis.
DCS has also been shown to improve learning and enhance memory in some situations, and has been the subject of many patents and patent applications covering neuropsychiatric disorders including Alzheimer's Disease (see, for example, Cordi, U.S. Pat. No. 5,061,721, and Tsai, U.S. Pat. No. 6,228,875), anxiety disorders (see, for example, Davis, U.S. Pat. No. 7,750,030), and depression (see McDevitt, U.S. Pat. No. 8,309,535). DCS has been widely studied in human clinical trials as a potential treatment for dementia conditions including Alzheimer's Disease, showing benefits in at least some of the clinical trials, but no significant benefit in others. For example, a multi-center, 410-patient clinical trial conducted by Searle Pharmaceuticals concluded that DCS at up to 50 mg daily dosing did not have a significant benefit for treatment of Alzheimer's Disease (Fakouhi et al., J Geriatr Psychiatry Neurol, October 1995, vol. 8, no. 4, pp. 226-230). A meta-analysis looking at numerous clinical studies with DCS and Alzheimer's Disease concluded that: “The lack of a positive effect of D-cycloserine on cognitive outcomes in controlled clinical trials with statistical power high enough to detect a clinically meaningful effect means that D-cycloserine has no place in the treatment of patients with Alzheimer's disease.” (Laake et al., Cochrane Database Syst Rev. 2002; (2): CD003153) However, a study from Tsai et al. concluded that 100 mg daily administration of DCS had a positive benefit on Alzheimer's Disease (Tsai et al., Am J Psychiatry. 1999 March; 156(3): 467-9).
DCS has shown promise in animal studies for treatment of other forms of dementia. For example, based on rat studies, DCS has been suggested as a candidate for treatment of frontotemporal dementia (Warmus et al., “Tau-Mediated NMDA Receptor Impairment Underlies Dysfunction of a Selectively Vulnerable Network in a Mouse Model of Frontotemporal Dementia”, The Journal of Neuroscience, 3 Dec. 2014, 34(49): 16482-16495) and also dementia related to Parkinson's Disease (Behav. Brain Res. 2011 Jun. 1; 219(2): 280-90).
While DCS is a partial agonist of the NMDA receptor, memantine is an antagonist of the NMDA receptor. Memantine is FDA-approved for treatment of Alzheimer's Disease, sold under the tradename NAMENDA® in the United States.
DCS, when administered daily for significant periods, induces physiological changes that reduce its activity. For example, Werner-Seidler and Richardson showed that the well-known ability of DCS to facilitate extinction learning is eliminated in rats if the rats have been exposed to DCS for 15 consecutive days. Moreover, antidepressants can have similar effects, and daily administration of imipramine for 15 days also blocked the ability of DCS to facilitate extinction learning (Werner-Seidler et al., “Effects of D-Cycloserine on Extinction: Consequences of Prior Exposure to Imipramine”, Biological Psychiatry, Volume 62, Issue 10, 15 Nov. 2007, Pages 1195-1197). Parnas et al. (Neurobiology of Learning and Memory, 83 (2005) 224-231) showed that administering DCS to rats for five consecutive days, followed by a conventional extinction learning paradigm two days later, significantly decreased the ability of DCS to facilitate extinction. In contrast, when DCS was administered for five consecutive days, followed by a conventional extinction learning paradigm 28 days later, the ability of DCS to facilitate extinction was restored. DCS also enhances development of tolerance to other compounds, including for example ethanol (see Khanna et al., CNS Drug Reviews, Vol. 5, No. 2, pp. 165-176).